US 5,349,066 AGranted

Bifunctional linking compounds, conjugates and methods for their production

AssigneeBristol-Myers Squibb Company

InventorsTakushi Kaneko, David Willner, Ivo Monkovic, Robert S. Greenfield, Gary R. Braslawsky

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Abstract

The present invention provides novel N-substituted hydrazine bifunctional compounds, novel N-substituted hydrazone derivatives of a cytotoxic reagent incorporating the bifunctional compounds, novel conjugates containing at least one cytotoxic reagent molecule reacted with the bifunctional compound and bound to a molecule reactive with a target cell population, methods for their production, and pharmaceutical compositions and methods for delivering cytotoxic reagents to a target population of cells. The hydrazone bonds of the conjugates of the invention permit the release of free cytotoxic reagent from the conjugates in the acidic external or internal environment of the target cells. The bifunctional compounds, derivatives, conjugates and methods of the invention are useful in antibody-or ligand-mediated drug delivery systems for the preferential killing of a target cell population to treat diseases such as cancers, infections and autoimmune disorders.

Claims8

Dependent claims

A conjugate formed by combining at least one molecule containing a free carbonyl group and at least one molecule containing a sulfhydryl group with at lease one of the following compounds:

(a) a bifunctional N-substituted hydrazine compound having the formula:
H.sub.2 NNHCONH(CH.sub.2).sub.n SSR.sup.8
wherein n is an integer from 1 to 10;
and R.sup.8 is ##STR7## wherein X is NO.sub.2 or halogen;
(b) a N-substituted hydrazine bifunctional compound having the formula:
H.sub.2 NNHCONHNHCONH(CH.sub.2).sub.n SSR.sup.8
wherein n is an integer from 1 to 10;
and R.sup.8 is ##STR8## wherein X is H, NO.sub.2 or halogen;
(c) a N-substituted hydrazine bifunctional compound having the formula:
H.sub.2 NNHCSNH(CH.sub.2).sub.m CH.dbd.CH(CH.sub.2).sub.n SSR.sup.8
wherein m, n are integers from 1 to 10, which are the same or different;
and R.sup.8 is ##STR9## wherein X is H, NO.sub.2 or halogen;
or (d) a N-substituted hydrazine bifunctional compound having the formula:
H.sub.2 NNHCOO(CH.sub.2).sub.n SSR.sup.8
wherein n is an integer from 1 to 10;
and R.sup.8 is ##STR10## wherein X is H, NO.sub.2 or halogen;
or (e) a N-substituted hydrazine bifunctional compound having the formula:
H.sub.2 NNH--Ar--CONH(CH.sub.2).sub.n SSR.sup.8
wherein n is an integer from 1 to 10;
and R.sup.8 is ##STR11## wherein X is NO.sub.2 or halogen and Ar is ##STR12##

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/865,062Filed 8 Apr 1992 · division
Priority: 14 May 1990
Granted: 20 Sep 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07H 15/252
Condensed ring systems having three or more rings: naphthacene radicals, e.g. daunomycins, adriamycins
A61K 47/65
The modifying agent being a protein, peptide or polyamino acid: peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
A61K 47/6809
The drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense: antibiotics, e.g. antitumor antibiotics…
A61K 47/6889
The modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment: conjugates wherein the antibody being the…

Family

Serial522,996Parent of this division · filed 14 May 1990
US 5,137,877 AParent of this division
US 5,349,066 AThis patent

From the US filing history. Foreign family members aren’t listed.

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